title: WNT/β-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production.
abstract: Primary aldosteronism (PA) is the main cause of secondary hypertension, resulting from adrenal aldosterone-producing adenomas (APA) or bilateral hyperplasia. Here, we show that constitutive activation of WNT/β-catenin signalling is the most frequent molecular alteration found in 70% of APA. We provide evidence that decreased expression of the WNT inhibitor SFRP2 may be contributing to deregulated WNT signalling and APA development in patients. This is supported by the demonstration that mice with genetic ablation of Sfrp2 have increased aldosterone production and ectopic differentiation of zona glomerulosa cells. We further show that β-catenin plays an essential role in the control of basal and Angiotensin II-induced aldosterone secretion, by activating AT1R, CYP21 and CYP11B2 transcription. This relies on both LEF/TCF-dependent activation of AT1R and CYP21 regulatory regions and indirect activation of CYP21 and CYP11B2 promoters, through increased expression of the nuclear receptors NURR1 and NUR77. Altogether, these data show that aberrant WNT/β-catenin activation is associated with APA development and suggest that WNT pathway may be a good therapeutic target in PA.
authors.affiliation: Clermont Université, Université Blaise Pascal, GReD, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Annabel
authors.initials: A
authors.lastname: Berthon
authors.forename: Coralie
authors.initials: C
authors.lastname: Drelon
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Sheerazed
authors.initials: S
authors.lastname: Boulkroun
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Benoît
authors.initials: B
authors.lastname: Samson-Couterie
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Zennaro
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Plouin
authors.forename: Seham
authors.initials: S
authors.lastname: Skah
authors.forename: Michelina
authors.initials: M
authors.lastname: Plateroti
authors.forename: Hervé
authors.initials: H
authors.lastname: Lefèbvre
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sahut-Barnola
authors.forename: Marie
authors.initials: M
authors.lastname: Batisse-Lignier
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lefrançois-Martinez
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Antoine
authors.initials: A
authors.lastname: Martinez
authors.forename: Pierre
authors.initials: P
authors.lastname: Val
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000150:complications / Q000378:metabolism*; D018246:Adrenocortical Adenoma / Q000150:complications / Q000378:metabolism*; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006929:Hyperaldosteronism / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000450:Aldosterone; D019405:Cytochrome P-450 CYP11B2; D008565:Membrane Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins